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In situ recruitment of antigen-presenting cells by intratumoral GM-CSF gene delivery

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Abstract

Proper antigen presentation is paramount to the induction of effective and persistent antitumor immune responses. In a murine model of hepatic metastasis of colon cancer, we found that the numbers of in situ mature dendritic cells (DCs) and macrophages in tumor-infiltrating leukocytes (TILs) were significantly increased in mice treated with the combination therapy of herpes simplex virus thymidine kinase, interleukin 2, and GM-CSF genes when compared with control groups without GM-CSF treatment. Significantly higher levels of IFN-γ, MIP-1α, mIL-12, and GM-CSF were detected in the tumor after the combination therapy. T cells isolated from the combination therapy–treated mice exhibited higher ex vivo direct CTL activity than those from other treatment groups. Antigen-presenting cells (APCs) enriched from the TILs and liver of the combination therapy–treated mice induced higher levels of proliferation by the splenocytes from long-term surviving mice that had been cured of tumors at early time points (days 4 and 7) whereas significant APC activity was only observed in the spleen at the latter time point (day 7, 14) after the combination therapy. In contrast, APCs isolated from tk or tk + IL-2–treated mice did not induce any significant proliferation. Subcutaneous injection of fluorescence-labeled latex microspheres followed by the combination therapy showed a similar sequential trafficking of microspheres, day 4 after the combination therapy to tumor and day 14 to spleen. The results suggest that APCs recruited by intratumoral gene delivery of GM-CSF can capture antigens, mature to a stage suitable for antigen presentation, and subsequently migrate to the spleen where they can efficiently stimulate antigen-specific T cells.

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Acknowledgements

The authors thank Drs Savio L.C. Woo, Simon Hall, Gwendalyn J. Randolph, and Celia Divino for helpful discussion; Ms Yunjuan Zang, Yongmei Gan, and Mr Khiem Pham-Nguyen for technical assistant; and Miss Marcia Messick for editorial assistance. This research was supported in part by the Sharp foundation and NIH grants RO1 75175, RO1 70337, and RO1 84404 to S.-H. Chen.

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Authors and Affiliations

  1. Carl C. Icahn Institute for Gene Therapy and Molecular Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA

    Ping-Ying Pan, Yu Li, Qingsheng Li, Pedi Gu & Shu-Hsia Chen

  2. Department of Pathology, Mount Sinai School of Medicine, New York, NY 10029, USA

    Swan Thung

  3. Department of Surgery, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland

    Olivier Martinet

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  1. Ping-Ying Pan
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  2. Yu Li
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  3. Qingsheng Li
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  4. Pedi Gu
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  6. Swan Thung
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  7. Shu-Hsia Chen
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Correspondence to Shu-Hsia Chen.

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P.-Y. Pan and Y. Li contributed equally to this work.

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Pan, PY., Li, Y., Li, Q. et al. In situ recruitment of antigen-presenting cells by intratumoral GM-CSF gene delivery. Cancer Immunol Immunother 53, 17–25 (2004). https://doi.org/10.1007/s00262-003-0417-4

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  • DOI: https://doi.org/10.1007/s00262-003-0417-4

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